Thyroid transcription factor-1 (TTF-1) and surfactant apoprotein A (SP-A) belong to tissue-specific markers expressed in the normal respiratory epithelium. Both proteins are expressed in some lung carcinomas, and they have potential diagnostic use. We performed an immunohistochemical study on 109 tumors to determine the usefulness of monoclonal SP-A (PE-10) and TTF-1 (8G7G3/1) antibodies in distinguishing primary and metastatic lung carcinomas ( n=54) from a broad spectrum of nonpulmonary tumors ( n=55). An immunoperoxidase method using a streptavidin-biotin kit was applied on paraffin sections. We found positive results for TTF-1 and SP-A in 75% and 46% of pulmonary adenocarcinomas and in 50% and 25% of pulmonary non-neuroendocrine large cell carcinomas (LCCs), respectively. Small cell lung carcinomas were TTF-1 positive in 89% of cases and completely negative for SP-A. Squamous cell carcinomas and carcinoid tumors were negative for both proteins. In the group of nonpulmonary tumors, TTF-1 was detected in 8 of 11 thyroid carcinomas and SP-A in 1 of 6 colorectal carcinomas. Other tumors, including seven cases of pleural mesothelioma, were negative for both TTF-1 and SP-A. The expression of both antibodies was independent of primary and metastatic sites of the tumor. We observed a significant decrease of SP-A immunoreactivity in poorly differentiated lung adenocarcinomas. The combination of anti-TTF-1 with anti-SP-A does not increase the diagnostic usefulness of TTF-1 alone. Because of its diagnostic utility TTF-1 should be added to a panel of antibodies used for assessing tumors of unknown origin.